Angiosarcomas, Soft Tissue Sarcoma
Conditions
Brief summary
This is an open-label, single-arm, multi-center, Phase 2 study with Paclitaxel in combination with Bevacizumab in patients with Unresectable or Metastatic Angiosarcoma. The study aims to determine the safety and effectiveness of combining two drugs Paclitaxel and Bevacizumab in the treatment of Angiosarcoma that cannot be removed by surgery, or has spread to other parts of your body. The primary objective is to evaluate 4month non progression rate. The secondary objective is to evaluate overall response rate after 3rd and 6th cycle, median duration of response, 6th and 12th month survival, toxicity of Paclitaxel and Bevacizumab combination, toxicity of maintenance Bevacizumab and to collect paraffin-embedded tumor blocks for angiogenesis markers and tissue microarray.
Detailed description
Regimen A versus B was chosen at the discretion of the treating physician. Both groups were analyzed together as far as outcome. Patients were to receive paclitaxel 200 mg/m2 intravenously over 3 hours every 21 days (Regimen A) or pactlitaxel 90 mg/m2 weekly x 3 of a 28 day cycle (Regimen B) followed by bevacizumab 15 mg/kg intravenously over (cycle 1: 90 min; cycle 2: 60 min; cycles 3-6: 30 min) every 21 days x 6 cycles. Maintenance bevacizumab (MB) started after the completion of combination of paclitaxel and bevacizumab and it was given at a dose of 15 mg/kg intravenously once every 21 days for a maximum of 8 cycles. Patients were allowed to receive growth factors. Dose reductions were done based on hematologic and non-hematologic toxicities.
Interventions
DRUGBevacizumab
15 mg/kg, IV every 21 days x 6 cycles.
DRUGPaclitaxel
Regimen A / Treatment 1: 200 mg/m² IV over 3 hours every 21 days. Regimen B / Treatment 2: 90 mg/m² weekly x 3 of a 28-day cycle
Sponsors
Genentech, Inc.
Stanford University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Baseline measurements and evaluations must be obtained within 4 weeks of registration to the study. Abnormal PET scans will not constitute evaluable disease, unless verified by computed tomography (CT) scan or other appropriate imaging * At least 1 objective measurable disease parameter by Response Evaluation Criteria In Solid Tumors (RECIST) criteria * Unresectable locally advanced or metastatic angiosarcoma * ≤ 2 prior chemotherapeutic regimens for angiosarcoma * No prior paclitaxel, docetaxel, or bevacizumab for angiosarcoma (previous paclitaxel or docetaxel allowed if not given for angiosarcoma and more than 12 months has elapsed since last dose) * No evidence of other active malignancies other than carcinomas in-situ of the cervix or basal cell carcinoma of the skin within 6 months prior to registration * If history of deep venous thrombosis or pulmonary embolism, receiving a stable dose of anticoagulation therapy for at least 2 weeks prior to registration * Within 7 days prior to registration, use of any anti-platelet drugs, such as ticlopidine, clopidogrel, and cilostazol. The use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAID) is allowed * ECOG performance status 0 to 2 * Patients must have adequate organ function as evidenced by the following laboratory studies (within 2 weeks prior to registration): * Serum creatinine ≤ 2.0 mg/dL * Total bilirubin ≤ 2.0 x upper limit of normal (ULN). If documented hepatic involvement, can be ≤ 3 x ULN * Serum glutamic oxaloacetic transaminase (SGOT) or Aspartate aminotransferase (AST) \< 2 x ULN. If documented hepatic involvement, can be ≤ 5 x ULN * Absolute neutrophil count ≥ 1500/mm3 and platelet count \> 100,000/mm3 * Platelets ≤ 1.5 x ULN * International normalized ratio (INR) ≤ 1.5 x ULN * Partial thromboplastin time (PTT) ≤ 1.5 x ULN * Left ventricular ejection fraction ≥ 50% * ≥ 18 years * Women of childbearing potential must have a negative human chorionic gonadotropin (hCG) pregnancy test within 2 weeks prior to registration
Exclusion criteria
* Life expectancy \< 12 weeks * Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an another experimental drug study * Inadequately-controlled hypertension (defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg) * History of hypertensive crisis or hypertensive encephalopathy * New York Heart Association (NYHA) Grade II or greater congestive heart failure * History of myocardial infarction or unstable angina within 6 months prior to Day 1 * History of stroke or transient ischemic attack within 6 months prior to Day 1 * Known central nervous system (CNS) disease, except for treated brain metastasis. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded. * Significant vascular disease (eg, aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 * History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1 * Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) * Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study * Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1 * History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 * Serious, non-healing wound, active ulcer, or untreated bone fracture * Proteinuria as demonstrated by a urine protein: creatinine ratio (UPC) ratio ≥ 1.0 at screening * Known hypersensitivity to any component of bevacizumab * Active infection requiring parental antibiotics * Known human immunodeficiency virus (HIV) infection * Pregnant or breast feeding * Inability to comply with study and/or follow-up procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | 4 months | The primary objective of this study was to evaluate progression-free survival (PFS or non-progression rate) through 4 months from start of treatment. Progression is defined as ≥ 20% increase in the sum of the longest diameter of target lesions, as compared to the baseline measurements, and/or the appearance of one or more new lesion(s). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) at 12 Months | 12 months | Assessed as the number of subjects known to remain alive 12 months after study entry |
| Overall Response Rate After 3 Cycles | 12 weeks | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria, per protocol. Overall response rate (ORR) is the sum of the Complete Response (CR) + Partial Response (PR) rates. The ORR for participants after 3 cycles of treatment (12 weeks) is expressed as the number and proportion of subjects. RECIST Criteria * CR = Disappearance of all target lesions * PR = ≥ 30% decrease in the sum of the longest diameter of target lesions * Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s), * Stable disease (SD) = Small changes that do not meet any of the above criteria |
| Overall Response Rate After 6th Cycle | 6 Cycles | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria, per protocol. Overall response rate (ORR) is the sum of the Complete Response (CR) + Partial Response (PR) rates. The ORR for participants after 6 cycles of treatment (24 weeks) is expressed as the number and proportion of subjects. RECIST Criteria * CR = Disappearance of all target lesions * PR = ≥ 30% decrease in the sum of the longest diameter of target lesions * Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s), * Stable disease (SD) = Small changes that do not meet any of the above criteria |
| Overall Survival (OS) at 6 Months | 6 months | Assessed as the number of subjects known to remain alive 6 months after study entry |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen A Treatment 1 Participants were to receive paclitaxel 200 mg/m² intravenously over 3 hours every 21 days followed by bevacizumab 15 mg/kg intravenously over (cycle 1: 90 min; cycle 2: 60 min; cycles 3 to 6: 30 min) every 21 days x 6 cycles.
Maintenance bevacizumab (MB), 15 mg/kg once every 21 days intravenously for a maximum of 8 cycles, was initiated after the completion of paclitaxel + bevacizumab combination. | 9 |
| Regimen B Treatment 2 Patients were to receive paclitaxel 90 mg/m² weekly x 3 of a 28-day cycle followed by bevacizumab 15 mg/kg intravenously over (cycle 1: 90 min; cycle 2: 60 min; cycles 3 to 6: 30 min) every 21 days x 6 cycles.
Maintenance bevacizumab (MB), 15 mg/kg once every 21 days intravenously for a maximum of 8 cycles, was initiated after the completion of paclitaxel + bevacizumab combination. | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Inter-treatment Period | Did not start Cycle 4 | 0 | 3 |
| Screening | Screen Failure | 1 | 1 |
| Treatment Cycles 1 to 3 | Adverse Event | 0 | 1 |
| Treatment Cycles 1 to 3 | Discontinued, < 3 cycles treatment | 2 | 2 |
Baseline characteristics
| Characteristic | Total | Regimen A Treatment 1 | Regimen B Treatment 2 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 6 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 8 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 7 Participants | 8 Participants |
| Sex: Female, Male Female | 9 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 9 Participants | 4 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 8 / 8 | 8 / 8 |
| serious Total, serious adverse events | 8 / 8 | 4 / 8 |
Outcome results
Primary
Progression-free Survival (PFS)
The primary objective of this study was to evaluate progression-free survival (PFS or non-progression rate) through 4 months from start of treatment. Progression is defined as ≥ 20% increase in the sum of the longest diameter of target lesions, as compared to the baseline measurements, and/or the appearance of one or more new lesion(s).
Time frame: 4 months
Population: Includes all subjects that started treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen A Treatment 1 | Progression-free Survival (PFS) | 4 Participants without disease progression |
| Regimen B Treatment 2 | Progression-free Survival (PFS) | 5 Participants without disease progression |
Secondary
Overall Response Rate After 3 Cycles
Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria, per protocol. Overall response rate (ORR) is the sum of the Complete Response (CR) + Partial Response (PR) rates. The ORR for participants after 3 cycles of treatment (12 weeks) is expressed as the number and proportion of subjects. RECIST Criteria * CR = Disappearance of all target lesions * PR = ≥ 30% decrease in the sum of the longest diameter of target lesions * Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s), * Stable disease (SD) = Small changes that do not meet any of the above criteria
Time frame: 12 weeks
Population: Includes participants that complete 3 cycles of treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen A Treatment 1 | Overall Response Rate After 3 Cycles | Complete Response (CR) | 1 Participants |
| Regimen A Treatment 1 | Overall Response Rate After 3 Cycles | Stable Disease (SD) | 1 Participants |
| Regimen A Treatment 1 | Overall Response Rate After 3 Cycles | Partial Response (PR) | 2 Participants |
| Regimen A Treatment 1 | Overall Response Rate After 3 Cycles | Progressive Disease (PD) | 2 Participants |
| Regimen B Treatment 2 | Overall Response Rate After 3 Cycles | Progressive Disease (PD) | 1 Participants |
| Regimen B Treatment 2 | Overall Response Rate After 3 Cycles | Complete Response (CR) | 0 Participants |
| Regimen B Treatment 2 | Overall Response Rate After 3 Cycles | Partial Response (PR) | 2 Participants |
| Regimen B Treatment 2 | Overall Response Rate After 3 Cycles | Stable Disease (SD) | 2 Participants |
Secondary
Overall Response Rate After 6th Cycle
Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria, per protocol. Overall response rate (ORR) is the sum of the Complete Response (CR) + Partial Response (PR) rates. The ORR for participants after 6 cycles of treatment (24 weeks) is expressed as the number and proportion of subjects. RECIST Criteria * CR = Disappearance of all target lesions * PR = ≥ 30% decrease in the sum of the longest diameter of target lesions * Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s), * Stable disease (SD) = Small changes that do not meet any of the above criteria
Time frame: 6 Cycles
Population: Includes participants that complete 6 cycles of treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen A Treatment 1 | Overall Response Rate After 6th Cycle | Complete Response (CR) | 1 Participants |
| Regimen A Treatment 1 | Overall Response Rate After 6th Cycle | Stable Disease (SD) | 1 Participants |
| Regimen A Treatment 1 | Overall Response Rate After 6th Cycle | Partial Response (PR) | 2 Participants |
| Regimen A Treatment 1 | Overall Response Rate After 6th Cycle | Progressive Disease (PD) | 2 Participants |
| Regimen B Treatment 2 | Overall Response Rate After 6th Cycle | Partial Response (PR) | 0 Participants |
| Regimen B Treatment 2 | Overall Response Rate After 6th Cycle | Complete Response (CR) | 0 Participants |
| Regimen B Treatment 2 | Overall Response Rate After 6th Cycle | Progressive Disease (PD) | 1 Participants |
| Regimen B Treatment 2 | Overall Response Rate After 6th Cycle | Stable Disease (SD) | 1 Participants |
Secondary
Overall Survival (OS) at 12 Months
Assessed as the number of subjects known to remain alive 12 months after study entry
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A Treatment 1 | Overall Survival (OS) at 12 Months | 6 Participants |
| Regimen B Treatment 2 | Overall Survival (OS) at 12 Months | 6 Participants |
Secondary
Overall Survival (OS) at 6 Months
Assessed as the number of subjects known to remain alive 6 months after study entry
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A Treatment 1 | Overall Survival (OS) at 6 Months | 7 Participants |
| Regimen B Treatment 2 | Overall Survival (OS) at 6 Months | 8 Participants |